Select NSAIDs enhance peripheral nerve growth and calcium signaling through PPARγ activation

Peripheral nerve injuries (PNIs) are a significant health concern, affecting millions of individuals and result in debilitating sensory and motor deficits, as well as severe neuropathic pain. Treatment of PNIs depend on severity and gap length, with small gaps repaired by sutures and larger ones requiring autologous nerve grafting, the gold standard for bridging defects. However, autologous grafting also has significant limitations, including low recovery rates and complications such as neuroma formation. Tissue engineering and regenerative medicine offer promising alternatives but lack effective treatments directly enhancing nerve regeneration. Our previous research explored the potential of repurposing non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen and indomethacin, to promote peripheral nerve regeneration (PNR). These drugs demonstrated enhanced axonal growth and calcium signaling, suggesting a dual role in promoting neuronal recovery. The present study aimed to identify the underlying mechanism of this drug-mediated axonal growth. We hypothesized that ibuprofen and indomethacin function as peroxisome proliferator-activated receptor gamma (PPARγ) agonists, inhibiting RhoA activation and thus facilitating axonal growth. To test this, we performed immunostaining, Western blotting, and calcium imaging on dorsal root ganglion (DRG) explants treated with these drugs, both with and without PPARγ antagonists. We also investigated whether cyclooxygenase (COX) inhibition, the primary pain-relieving mechanism of NSAIDs, contributes to axonal growth. Our findings indicate that ibuprofen and indomethacin promote axonal growth through PPARγ activation, independent of COX inhibition, suggesting that targeting the PPARγ pathway could be a novel therapeutic strategy for enhancing nerve regeneration and improving outcomes for patients with PNIs.